Dr. Eileen Foy is a pediatric infectious disease physician with an interest in viral pathogenesis that stems from her graduate work in the Medical Scientist Training Program at the University of Texas, Southwestern Medical Center. Her objective in this current project is to combine her clinical and basic science interests in infectius diseases by studying how early events during enterovirus infection modulate the host cell environment to promote a productive infection. EV71 VP4 is a structural protein that forms the inner core of the viral capsid with a well-described role in facilitating viral entry. However, through her preliminary studies, Dr. Foy has shown that VP4 also interacts with important host cellular proteins suggesting that it has critical functions in modulating the intracellular host environment upon entry. Some of these interacting host proteins are involved in the regulation of cell death signaling pathways. Through a series of specific aims, Dr. Foy will examine the role of the EV71 VP4 protein in modulating cell death pathways through its interaction with important regulators of these processes. Initially, she will determine what structural elements in VP4 mediate the interaction with cell death pathway regulatory protein(s) (Aim1). She will then define the role of these host proteins in mediating cell death during enterovirus infection and examine the impact of VP4 on these processes (Aim 2). Finally, she will utilize a murine model of infection to examine the role of the interplay between VP4 and cell death pathways on enterovirus disease pathogenesis (Aim3). The goal of these studies is to understand the novel function(s) of VP4 early during infection in modulating the host environment, specifically regarding cell death pathways and to apply this knowledge to the design of therapeutics targeted to disrupt this critical viral function. This application will also provide the contextual basis for Dr. Foy's ongoing career development to transition to an independent investigator. Her research training will complement her prior laboratory experience and provide her with the technical and intellectual background in viral pathogenesis needed to facilitate independence. A carefully selected committee of internationally recognized scientists and physicians with expertise in virology, microbial pathogenesis, cell death pathways and clinical infectious diseases has been chosen to oversee her progression through this process. Her scientific development will also be enriched through attendance at UCSF courses in pertinent topics, several seminar series, departmental retreats and national and international scientific meetings. Additionally, Dr. Foy will attend career development seminars and workshops offered through UCSF. Lastly, she will support her clinical development through attending on the pediatric infectious diseases service, weekly clinical seminar series and meetings with her clinical mentor. At the end of this award period, Dr. Foy will have developed the necessary skills to launch her own research and clinical agenda as an independent investigator in the field of infectious diseases with a focus on viral pathogenesis.